The nitric acid esters of organic compounds, commonly known as nitrated organic compounds, are known and have been used as vasodilating agents for some time. Among these, the usefulness of mono- and di-nitrated isosorbide is well known, and furthermore, compounds with vascular and coronary activities based on substitution reactions of the free hydroxyl group of isosorbide mononitrate have been described.
Patent application WO 00/20420 describes isosorbide mononitrates wherein the free hydroxyl group is esterified with either carboxylic acids or with thioacids wherein said ester groups are in trans position with respect to the nitrate group.
Patent application WO 2005/037842 describes isosorbide mononitrates wherein the free hydroxyl group has been replaced by a wide range of substituents.
A particular class of compounds disclosed in these publications is represented by the following formula (A)
wherein one of A and B represents —ONO2 and the other represents —S—CO—R, wherein R is a C1-4 alkyl group, an aryl group or an aralkyl group, eventually substituted. According to these publications the disclosed dioxa-bicyclooctane compounds may be prepared by thioacetylation of a compound of formula (B):
wherein L represents a leaving group, isolating the thioacetylated product by chromatography, carrying out a nitration reaction, and then purifying the compounds of interest by another chromatographic treatment.
This preparation method affords less than 20% overall yield and involves chromatographic treatments after the thioacetylation step as well as after the nitration reaction. In addition the nitration step involved the use of a mixture of nitric acid, acetic acid and acetic anhydride which is unsatisfactory from a safety point of view. The need of chromatographic treatment and the use of unsafe nitrating agents are extremely disadvantageous for industrial-scale synthetic preparations. Furthermore, both the low yield and the purification by chromatography are highly undesirable from an economic point of view.